FUENTES BUSTOS, MARIA IGNACIA
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FUENTES BUSTOS, MARIA IGNACIA
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mifuentes@udd.cl
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57193308856

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Collagen VII maintains proteostasis in dermal fibroblasts by scaffolding TANGO1 cargo

2022 , Qingqing Cao , Grace Tartaglia , Michael Alexander , Pyung Hung Park , Shiv Poojan , Mehdi Farshchian , FUENTES BUSTOS, MARIA IGNACIA , Mei Chen , John A. McGrath , PALISSON ETCHARREN, FRANCIS , Julio Salas-Alanis , Andrew P. South

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Cells from discarded dressings differentiate chronic from acute wounds in patients with Epidermolysis Bullosa

2020 , FUENTES BUSTOS, MARIA IGNACIA , Christina Guttmann-Gruber , Birgit Tockner , Anja Diem , Alfred Klausegger , Glenda Cofré-Araneda , Olga Figuera , Yessia Hidalgo , Pilar Morandé , PALISSON ETCHARREN, FRANCIS , Boris Rebolledo-Jaramillo , YUBERO GONCALVEZ, MARIA JOAO , Raymond J. Cho , Heather I. Rishel , M. Peter Marinkovich , Joyce M. C. Teng , Timothy G. Webster , Marco Prisco , Luis H. Eraso , Josefina Piñon Hofbauer , Andrew P. South

AbstractImpaired wound healing complicates a wide range of diseases and represents a major cost to healthcare systems. Here we describe the use of discarded wound dressings as a novel, cost effective, accessible, and non-invasive method of isolating viable human cells present at the site of skin wounds. By analyzing 133 discarded wound dressings from 51 patients with the inherited skin-blistering disease epidermolysis bullosa (EB), we show that large numbers of cells, often in excess of 100 million per day, continually infiltrate wound dressings. We show, that the method is able to differentiate chronic from acute wounds, identifying significant increases in granulocytes in chronic wounds, and we show that patients with the junctional form of EB have significantly more cells infiltrating their wounds compared with patients with recessive dystrophic EB. Finally, we identify subsets of granulocytes and T lymphocytes present in all wounds paving the way for single cell profiling of innate and adaptive immune cells with relevance to wound pathologies. In summary, our study delineates findings in EB that have potential relevance for all chronic wounds, and presents a method of cellular isolation that has wide reaching clinical application.

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Extracellular Vesicles as Biomarkers for the Detection of a Tumor Marker Gene in Epidermolysis Bullosa-Associated Squamous Cell Carcinoma

2018 , Yuchen Sun , Katharina Woess , Melanie Kienzl , Victoria M. Leb-Reichl , Andrea Feinle , Monika Wimmer , Roland Zauner , Verena Wally , Ursula Luetz-Meindl , Jemima E. Mellerio , Ignacia Fuentes , Andrew P. South , Johann W. Bauer , Julia Reichelt , Tomomi Furihata , Christina Guttmann-Gruber , Josefina Piñón Hofbauer

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Maintenance of chronicity signatures in fibroblasts isolated from recessive dystrophic epidermolysis bullosa chronic wound dressings under culture conditions

2023 , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , Evelyng Catalán , Gabriel Garrido , Pilar Morandé , CASTILLO BENNETT, JIMENA VICTORIA , Catalina Muñoz , Glenda Cofré , HUANG, YA LIN , Bárbara Cuadra , Paola Murgas , Margarita Calvo , Fernando Altermatt , Andrew P. South , YUBERO GONCALVEZ, MARIA JOAO , PALISSON ETCHARREN, FRANCIS , EZQUER, EDUARDO MARCELO , FUENTES BUSTOS, MARIA IGNACIA

Abstract Background Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare inherited skin disease caused by variants in the COL7A1 gene, coding for type VII collagen (C7), an important component of anchoring fibrils in the basement membrane of the epidermis. RDEB patients suffer from skin fragility starting with blister formation and evolving into chronic wounds, inflammation and skin fibrosis, with a high risk of developing aggressive skin carcinomas. Restricted therapeutic options are limited by the lack of in vitro models of defective wound healing in RDEB patients. Results In order to explore a more efficient, non-invasive in vitro model for RDEB studies, we obtained patient fibroblasts derived from discarded dressings) and examined their phenotypic features compared with fibroblasts derived from non-injured skin of RDEB and healthy-donor skin biopsies. Our results demonstrate that fibroblasts derived from RDEB chronic wounds (RDEB-CW) displayed characteristics of senescent cells, increased myofibroblast differentiation, and augmented levels of TGF-β1 signaling components compared to fibroblasts derived from RDEB acute wounds and unaffected RDEB skin as well as skin from healthy-donors. Furthermore, RDEB-CW fibroblasts exhibited an increased pattern of inflammatory cytokine secretion (IL-1β and IL-6) when compared with RDEB and control fibroblasts. Interestingly, these aberrant patterns were found specifically in RDEB-CW fibroblasts independent of the culturing method, since fibroblasts obtained from dressing of acute wounds displayed a phenotype more similar to fibroblasts obtained from RDEB normal skin biopsies. Conclusions Our results show that in vitro cultured RDEB-CW fibroblasts maintain distinctive cellular and molecular characteristics resembling the inflammatory and fibrotic microenvironment observed in RDEB patients’ chronic wounds. This work describes a novel, non-invasive and painless strategy to obtain human fibroblasts chronically subjected to an inflammatory and fibrotic environment, supporting their use as an accessible model for in vitro studies of RDEB wound healing pathogenesis. As such, this approach is well suited to testing new therapeutic strategies under controlled laboratory conditions.

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Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma

2019 , Velina S. Atanasova , Celine Pourreyron , Mehdi Farshchian , Michael Lawler , Christian A. Brown , Stephen A. Watt , Sheila Wright , Michael Warkala , Christina Guttmann-Gruber , Josefina Piñón Hofbauer , FUENTES BUSTOS, MARIA IGNACIA , Marco Prisco , Elham Rashidghamat , Cristina Has , Julio C. Salas-Alanis , Francis Palisson , Alain Hovnanian , John A. McGrath , Jemima E. Mellerio , Johann W. Bauer , Andrew P. South

Abstract Purpose: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. Results: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. Conclusions: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.

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APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa

2018 , Raymond J. Cho , Ludmil B. Alexandrov , Nicoline Y. den Breems , Velina S. Atanasova , Mehdi Farshchian , Elizabeth Purdom , Tran N. Nguyen , Cristian Coarfa , Kimal Rajapakshe , Marco Prisco , Joya Sahu , Patrick Tassone , Evan J. Greenawalt , Eric A. Collisson , Wei Wu , Hui Yao , Xiaoping Su , Christina Guttmann-Gruber , Josefina Piñón Hofbauer , Raabia Hashmi , Ignacia Fuentes , Stephen C. Benz , Justin Golovato , Erik A. Ehli , Christel M. Davis , Gareth E. Davies , Kyle R. Covington , Dedee F. Murrell , Julio C. Salas-Alanis , Francis Palisson , Anna L. Bruckner , William Robinson , Cristina Has , Leena Bruckner-Tuderman , Matthias Titeux , Marcel F. Jonkman , Elham Rashidghamat , Su M. Lwin , Jemima E. Mellerio , John A. McGrath , Johann W. Bauer , Alain Hovnanian , Kenneth Y. Tsai , Andrew P. South

Early-onset squamous cell carcinoma in recessive dystrophic epidermolysis bullosa patients is characterized by APOBEC mutagenesis.

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Reduced Microbial Diversity Is a Feature of Recessive Dystrophic Epidermolysis Bullosa-Involved Skin and Wounds

2018 , Ignacia Fuentes , Christina Guttmann-Gruber , Angeline Su Ling Tay , Josefina Piñón Hofbauer , Simon L.I.J. Denil , Julia Reichelt , Francis Palisson , John E.A. Common , Andrew P. South

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